IZUMENOLIDE-A NOVEL β-LACTAMASE INHIBITOR PRODUCED BY MICROMONOSPORA

II. BIOLOGICAL PROPERTIES

Abstract

Izumenolide is a potent inhibitor of β-lactamases, especially from Gram-negative bacteria. The I₅₀ value of 0.01 μg/ml for TEM-2 β-lactamase, after 10 min preincubation, corresponds to a ratio of 7.6 moles inhibitor per mole of enzyme. The initial inhibitory reaction with TEM-2 β-lactamase exhibits mixed reaction kinetics, suggesting a possible overlapping binding site with the active center. TEM-2 β-lactamase is irreversibly inactivated by izumenolide in a biphasic reaction. Carbenicillin offers partial protection against inactivation. izumenolide exhibits limited antibiotic activity against some Gram-negative bacteria. Against β-lactamase producing bacteria izumenolide provides protection to ampicillin and cephaloridine but the protection is limited due to permeability problems associated with izumenolide entry into the cells.